JP2000001403A - Release-controlling composition for bioactive agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a release-controlling composition for a bioactive agent which is inexpensive, is adaptable to widespread, protected objects such as air cleaners, can release a bioactive agent in a controlled state and is useful for preventing the fungi on and in the protected objects from growing by including both a bioactive agent and a specific calixarene compound. SOLUTION: This release-controlling composition for a biostatic agent is prepared by including (A) a biostatic agent (pref. 4,5-dichloro-2-n-octyl-3-isothiazolone, etc.), and (B) a calixarene compound of the formula [X-X and Y-Y are each H or the like; (n) is 1-7; (m), (o), (p) and (z) are each 1-3], pref. 2,8,14,20- tetrapropylpentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28 ),9,11,13(27),15,17,19(26),21,23- dodecaen-4,6,10,12,16,18,22,24-octol, etc., pref. in the weight content ratio of (1:10)-(9:1).

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates generally to controlled release compositions of biologically active compounds. More specifically, the present invention relates to control the release of a biologically active compound.
c) specific calixarene compounds (calixa)
line compound).

[0002] Controlled release of biologically active compounds to the subject to be protected is important in the field of biologically active compounds. Typically, when a bioactive compound is added to a subject to be protected, the compound is released rapidly, whether or not it is needed. In controlled release compositions, the biologically active compound is provided in a manner that is more suited to the needs of the compound. In this way, only the required amount of the biologically active compound is released into the subject to be protected. Controlled release reduces cost, reduces toxicity, and increases efficiency.

[0003] Various methods for controlling the release are known. Such methods include encapsulating the bioactive substance, adsorbing the bioactive substance on an inert carrier such as silica gel, encapsulating the bioactive substance, and the like.

[0004] All of these methods are expensive for a wide range of commercial applications, have limited compatibility with controlled release methods for the compounds to be released or the objects to be protected, There are disadvantages, such as limited degree of control of the release of the active compound. For example, if the formation of the inclusion compound depends on the solvent, the choice of solvents that can be used is limited. A further challenge for inclusiveness is
In some cases, the solvent is complexed rather than the desired biologically active compound. For example, Suzuki et al. European Patent 709358A discloses the incorporation of isothiazolones using tetrakisphenol compounds. Although these compositions achieve some degree of controlled release of the isothiazolone, the degree of control is limited and the tetrakisphenol compounds used to form the inclusion compounds are very expensive. Suzuki et al. Did not discuss calixarene compounds. Kurita Kogyo's Japanese Patent Publication Hei 7-31
No. 91 discloses isothiazolone and 5,5'-
Disclosed are inclusion compounds with dichloro-2,2'-dihydroxydiphenylmethane. 5,5'-dichloro-2,
Since 2'-dihydroxydiphenylmethane is banned in some countries, it provides only a limited solution.

[0005] Thus, compared to currently available methods, it is cheaper and more compatible with a wider range of protected objects,
There remains a need for controlled release compositions of biologically active compounds that achieve more controlled release of the biologically active compound.

[0006] The present invention provides a controlled release composition comprising a biologically active compound and a calixarene compound having the following structural formula:

Embedded image

Where X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y
² , Y ³ and Y ⁴ are independently hydrogen, cyano, nitro,
Halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ )
Alkynyl, phenyl, substituted phenyl, _{(C 7} -
X ¹ and Y selected from C ₁₀ ) aralkyl, substituted (C ₇ -C ₁₀ ) aralkyl, NR ² R ³ , SR ⁴ ;
^{1, X 2} and ^Y 2, ^{X 3} and ^{Y 3,} and ^{X 4} and ^{Y 4} bonded to 5-membered - or 6-membered - can form a ring; R and ^{R 1} are independently hydrogen, (C ₁ -C ₈₎
Alkyl, cyclopropyl, phenyl, substituted phenyl,
(C ₇ -C ₁₀ ) aralkyl, substituted (C ₇ -C ₁₀ )
R ² , R ³ , and R ⁴ are independently selected from hydrogen, (C ₁ -C ₄ ) alkyl, phenyl, and substituted phenyl; n = 1-7, and m,
o, p, and z are independently selected from 1-3.

[0008] The present invention further relates to providing a method of preventing and inhibiting the growth of microorganisms in a subject, comprising introducing an effective amount of the above composition onto or into the subject to be protected. The present invention further relates to providing a method of inhibiting and inhibiting the growth of marine organisms in a structure, comprising introducing an effective amount of the composition described above or into the structure to be protected. . The present invention further relates to providing a method of inhibiting and inhibiting the growth of fungi, plants and insects, comprising introducing an effective amount of the composition described above or into the subject to be protected.

Throughout this specification, the following terms have the following meanings, unless explicitly indicated otherwise in the description. The term "biologically active compound" refers to a microbicide,
Refers to marine antifouling agents and pesticides. The term "microbicide" refers to a compound capable of inhibiting or controlling the growth of microorganisms on a subject. The term "microorganism" includes, but is not limited to, fungi, bacteria and algae.

"Marine antifouling agents" include algicides and molluscicides.
"Marine antifouling activity" is intended to include both prohibition or control of the growth of marine organisms. Marine organisms controlled by marine antifouling agents suitable for use in the present invention include hard fouling organisms.
g organisms) and soft fouling organisms (sof)
t fouling organisms). Generally speaking, the term "soft fouling organisms" refers to plants and plants such as slime, algae, kelp, soft corals, tunicates, hydropolyps, sponges, and anemones. Refers to vertebrates (invertebrates), and the term "hard fouling organisms"
RNacles, tubeworms and molluscs, which refer to invertebrates with certain types of hard outer shells.

[0011] The term "pesticides" refers to agricultural fungicides, herbicides.
And insecticides. Terminology for "agricultural fungicides"
In fungal applications such as plant and soil treatment.
Means a compound that can inhibit or control growth
You. The term "herbicide" is used to inhibit the growth of certain plants or
A compound that can be controlled. "Pesticide"
The term refers to a compound capable of controlling insects.
The term "alkyl" refers to linear, branched, cyclic and those
Including combinations of For "halogen" or "halo"
The terms include fluorine, chlorine, bromine, and iodine. "Replace
The terms “enyl” and “substituted aralkyl” refer to aromatic rings
One or more hydrogens are cyano, hydroxy, (C₁−
C₄) Alkyl, nitro, mercapto, (C ₁-C₄)
Alkylthio, halo, and (C₁-C₄) Alkoxy
Refers to those substituted with another substituent such as all
The amounts are by weight unless otherwise indicated. all
The range of% by weight includes the numerical value. In this specification
The following abbreviations are used: mg = milligram, m
L = milliliter, L = liter, HPLC = high-speed liquid
Chromatography, rpm = number of revolutions per minute, D
I water = deionized water, ppm = parts per million.

[0012] Biologically active compounds useful in the present invention include:
It is a hydrogen bond acceptor. That is, it is a compound having one or more atoms selected from nitrogen, oxygen, fluorine or a mixture thereof. Nitrogen or oxygen may be single or multiple bonds, such as carbonyl, imine, nitrile, hydroxy, amide, alkoxy, ester,
Examples include ether or amine groups.

In the present invention, preferred microbicides include 5-chloro-2-methyl-3-isothiazolone;
-Methyl-3-isothiazolone; 2-n-octyl-3
-Isothiazolone; 4,5-dichloro-2-n-octyl-3-isothiazolone; 3-iodo-2-propynylbutyl carbamate; 1,2-dibromo-2,4-
Dicyanobutane; methylenebis (thiocyanate); 2
-Thiocyanomethylthiobenzothiazole; tetrachloroisophthalonitrile; 5-bromo-5-nitro-1,
3-dioxane; 2-bromo-2-nitropropanediol; 2,2-dibromo-3-nitrilopropionamide; N, N'-dimethylhydroxyl-5,5'-dimethylhydantoin;bromochlorodimethylhydantoin;-Benzisothiazolin-3-one; 4,5
-Trimethylene-2-methyl-3-isothiazolone; 5
-Chloro-2- (2,4-dichlorophenoxy) phenol; and 3,4,4'-trichlorocarbanilide.

Suitable marine antifouling agents in the present invention include, but are not limited to: manganese ethylenebisdithiocarbamate;
Zinc dimethyl dithiocarbamate; 2-methyl-
4-tert-butylamino-6-cyclopropylamino-s
-Triazine; 2,4,5,6-tetrachloroisophthalonitrile; N, N-dimethyldichlorophenylurea;
Zinc ethylenebisdithiocarbamate; copper thiocyanate; 4,5-dichloro-2-n-octyl-3-isothiazolone; N- (fluorodichloromethylthio)-
Phthalimide; N, N-dimethyl-N′-phenyl-
N'-fluorodichloromethylthio-sulfamide; zinc 2-pyridinethiol-1-oxide; tetramethylthiuram disulfide; 2,4,6-trichlorophenylmaleimide; 2,3,5,6-tetrachloro-4- (methylsulfonyl ) -Pyridine; 3-iodo-
2-propynylbutyl carbamate; diiodomethyl p-tolyl sulfone; bisdimethyldithiocarbamoyl zinc ethylenebisdithiocarbamate; phenyl (bispyridyl) bismuth dichloride; 2- (4-thiazolyl) -benzimidazole; pyridine triphenylborane; phenylamide; halopropargyl Compound; or 2-haloalkoxyaryl-3-isothiazolone. Suitable 2-haloalkoxyaryl-3-isothiazolones include, but are not limited to, the following compounds: 2- (4-trifluoromethoxyphenyl) -3-isothiazolone; 2- (4-trifluoromethoxyphenyl ) -5-Chloro-3-isothiazolone; and 2- (4-trifluoromethoxyphenyl) -4,5-dichloro-3-isothiazolone.

Suitable agricultural fungicides in the present invention include, but are not limited to, dithiocarbamates and derivatives such as ferbam, ziram,
Maneb, mancoze
b), zineb, propineb (propi)
neb), metham, thiram (thir)
a), a complex of zineb and polyethylenethiuram disulfide, dazomet; and mixtures thereof with copper salts; dinocap
ap), binapacrylyl, and nitrophenol derivatives such as 2-sec-butyl-4,6-dinitrophenylisopropyl carbonate;
Captan, Folpet
et), glyodine, dithianon, thioquinox (thio)
quinox), benomyl, thiabendazole, vinolozolin, iprodione (ip
rodione), procymidone
ne), triadimenol (triadimeno)
l), triadimefon, bitertanol, fluoroimide, triarimol (tr)
iarimol), cycloheximide (cycloheide)
ximide), etirimol (ethirimo)
l), dodemorph, dimethomorph, thifluzamide, and quinomethionate
A heterocyclic structure such as: chloranil
il), dichlone, chloroneb, tricamb
a), various halogenated fungicides such as dichloran, and polychloronitrobenzene; fungicidal antibiotics such as griseofulvin, kasugamycin and streptomycin; diphenylsulfone, dodine, methoxyl.
xyl), various fungicides such as 1-thiocyano-2,4-dinitrobenzene, 1-phenylthiosemicarbazide, thiophanate-methyl and cymoxanil; and furalaxyl, ciproflram, offlace, Acylalanines such as benalaxyl and oxadixyl; fraginam, flumetova, phenylbenzamide derivatives as disclosed in EP 578586 A1, EP 550
An amino acid derivative such as the valine derivative disclosed in 788A1, methyl (E) -2- (2- (6-
Methoxy acrylates such as (2-cyanophenoxy) pyrimidin-4-yloxy) phenyl) -3-methoxyacrylate; benzo (1,2,3) thiadiazole-7-carbothioic acid S-methyl ester; propamocarb; imazalil; carbendazim Microbutanil; fenbuconazole; tridemorph; pyrazophos; fenarimol; fenpiclonil; pyrimethanil.

Suitable herbicides in the present invention include, but are not limited to: carboxylic acid derivatives such as benzoic acid and salts thereof; phenoxy and phenyl substituted carboxylic acids and their salts. Salts; trichloroacetic acid and salts thereof; carbamic acid derivatives such as ethyl-N, N-di (n-propyl) thiocarbamate and pronamide; substituted ureas, substituted triazines, oxyfluorfen
n) and diphenyl ether derivatives such as fluoroglycophene, anilides such as propanil; oxyphenoxy herbicides, uracils, nitriles, and other organic herbicides such as dithiopy
thiopyr) and thiazopyr (thiazopy)
r).

Suitable insecticides in the present invention include, but are not limited to, acephate, aldicarb, α-cypermethrin, azinphos-methyl, bifenthrin, binapacryl, buprofezin, carbaryl ( carbary
1), carbofuran, cartap, chloropyrifos, chloropyrifosmethyl, clofenthedine, cyfluthrin, cyhexatin, cypermethrin, cyphenothrin, deltamethrin, demeton, demeton-S-methyl, demeton-
O-methyl, demeton-S, demeton-S-methylsulfoxide, demefion-O, demefion-S, diarifone, diazinone, dicophor (dicofo)
l), dicrotophos, diflubenzuron, dimethoate, dinocap, endosulfan, endothione,
Esfenvalerate, Ethiophenecarb, Ethion, Ethate-methyl
l), etoprop, etrimfos, fenamifos, fenazaflow, fenbutatin-oxide, fenitrothion, phenoxycarb, fensulfotion, fenthion, fenvalerate, flucycloxuron, flufenoxuron, fulvalinate, phonofos, fosmethirane, fratiothiocarb, hexithizox, Isazofos, isofenfos, isoxathion, metamidofos, methidathion, methiocarb,
Methomyl, methyl parathion, mevinfos, mexacarbate, monocrotofos, nicotine, omethoate, oxamil, parathion, permethrin, folate, fosalon, fosmet, fosfamidon, pirimicarb, pirimifos-ethyl, profenofos, promecarb, propargite, pyridaben resmet Rotenone, Tebufenozide, Temefos, T
EPP, terbufos, thiodicarb, tolclofos-methyl, triazamate, and bamidione.

[0018] The bioactive compound is preferably a microbicide or a marine antifoulant. Particularly preferably, 2-methyl-
3-isothiazolone; 5-chloro-2-methyl-3-isothiazolone; 2-n-octyl-3-isothiazolone; 4,5-dichloro-2-n-octyl-3-isothiazolone; benzisothiazolone; 4,5-trimethylene -3-isothiazolone; 3-iodo-2-propynylbutylcarbamate; 5-chloro-2- (2,4-dichlorophenoxy) phenol; and 3,4,4'-trichlorocarbanilide.

[0019] Although useful calixarene compound in the present invention include the following, but not limited to: 2,8,14,20- tetrapropyl penta cyclo [19.3.1.1 ^{3 , 7} . ^19,13 .
1 ^15,19 ] octacosa-1 (25), 3,5,7
(28), 9, 11, 13 (27), 15, 17, 19
(26), 21,23-dodekaene-4,6,10,1
2,16,18,22,24-octol; 2,8,1
4,20-tetramethylpentacyclo [19.3.1.
^13,7 . ^19,13 . 1 ^15,19 ] octacosa-1
(25), 3, 5, 7 (28), 9, 11, 13 (2
7), 15, 17, 19 (26), 21,23-dodecaene-4,6,10,12,16,18,22,24-
Octol; 2,8,14,20-tetraphenylpentacyclo [19.3.1.1 ^3,7 . ^19,13 . 1
^15,19 ] octacosa-1 (25), 3,5,7 (2
8), 9, 11, 13 (27), 15, 17, 19 (2
6), 21,23-dodecaene-4,6,10,12,
16,18,22,24-octol; and 2,8,
14,20-tetra-t-butylpentacyclo [19.
3.1.1 ^3,7 . ^{19, 13} . 1 ^15,19 ] octacosa-1 (25), 3,5,7 (28), 9,11,1
3 (27), 15, 17, 19 (26), 21, 23
Dodecaene-4,6,10,12,16,18,22,
24-octol.

The calixarene compounds useful in the present invention are generally commercially available or can be prepared by methods known from the literature. For example, H
ogberg, J .; Org. Chem. , 45,449
8-4500 (1980); Hogberg, J. et al. A
m. Chem. Soc. , 102, 6046-6050
(1980); and Tunstad et al. Org.
Chem. , 54, 1305-1312 (1989), disclose methods for preparing various calixarene compounds, and the teachings of the methods for preparing calixarene compounds of the present invention are incorporated herein by reference.

The composition of the present invention can be prepared by mixing a solution of a biologically active compound and a solution of a calixarene compound. Alternatively, a bioactive compound or a calixarene compound may be neatly added to a solution of the other ingredients.
at) can also be added. For example, the calixarene compound can be added neat to the solution of the biologically active compound. The solvent can be removed by any means, such as removal under reduced pressure, to obtain a solid or liquid composition. The solvent used to dissolve the biologically active compound can be the same or different from the solvent used to dissolve the calixarene compound. If different solvents are used to dissolve the bioactive compound and the calixarene compound, they are preferably miscible with each other. Mixed solvents can also be used.
Suitable solvents include alcohols such as methanol, ethanol, and propanol; esters such as ethyl acetate, butyl acetate; ketones such as acetone and methyl isobutyl ketone; nitriles such as acetonitrile, and the like. Alternatively, the biologically active compound or the calixarene compound, or both, can be mixed as a melt. If a melt is used to prepare the composition of the present invention, it is preferred to melt the bioactive compound and add the calixarene compound thereto. If the compositions according to the invention are oily, they are preferably dissolved in a carrier.

The calixarene compounds of the present invention may contain from 0.1% to 95% by weight based on the weight of the composition of the present invention.
Of biologically active compounds can be added. That is, the weight ratio of the biologically active compound to the calixarene compound is generally from 0.1: 99.9 to 95: 5. Preferably, the weight ratio is from 1:10 to 9: 1, more preferably 1: 1:
3 to 4: 1.

If the compounds do not react irreversibly or destabilize, are compatible with each other, and are compatible with the calixarene compound, one or more bioactive compounds are used in the compositions of the present invention. be able to. Controlling the release of a plurality of biologically active compounds has the effect of obtaining a broader spectrum of control than a single compound. This also reduces processing costs if more than one bioactive compound has to be used. If more than one bioactive compound is used, the total amount of bioactive compound to calixarene compound is generally from 0.1: 99 to 95: 5.

The composition of the present invention may include a carrier such as water, an organic solvent or a mixture thereof. Suitable organic solvent carriers include, for example, acetonitrile, ethyl acetate, butyl acetate, toluene, xylene, methanol, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, and glycol ether. But not limited to these. When the composition of the present invention is used for agricultural applications, the carrier is preferably an agriculturally acceptable carrier.

The compositions of the present invention are useful wherever a biologically active compound is useful. Where the bioactive compound is a microbicide, the compositions of the present invention are useful for inhibiting and controlling the growth of bacteria, and microorganisms such as fungi, in a subject. The composition of the present invention is suitably used in all subjects requiring protection from microorganisms. Suitable objects include, for example, cooling towers;
Mineral slurries; Pulp and paper processing fluids; Paper coatings; Swimming pools; Hot springs; Adhesives; Caulks; Mactics; Sealants; Agricultural adjuvant preservatives; Building products; Shampoos; disinfectants and disinfectants
Industrial or household compounded products; Soaps; Rinsing water for washing; Leather and leather products; Wood, such as sawn timber, squarewood, fiberboard, plywood, and wood composites;
Emulsions and dispersions; Paints, including marine paints; Varnishes, including marine varnishes; Latex; Odor control fluids; Coatings including; petroleum processing fluids; fuels;
Oilfield fluids; photographic chemicals; printing fluids
fluids); sanitizers;
Cleaning agents; textiles such as fibers; and textile products such as garments and carpets.

When the composition of the present invention comprises a microbicide,
It can be added directly to the subject to be protected, or even as a composition with a suitable carrier. Suitable carriers in microbicidal applications include
Water; organic solvents such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, xylene, toluene, acetone, methyl isobutyl ketone, or esters; or mixtures thereof, but are not limited thereto. The composition is a microemulsion, a microemulsion (micro
oemulsifiable concentrate
s), can be formulated as an emulsion, emulsion, or paste, or can be encapsulated.
The particular formulation will depend on the subject being protected and the particular microbicide used. Methods for preparing these formulations are known and standard methods can be used.

When the composition contains a microbicide, the amount of the composition according to the invention required to control microorganisms and to inhibit their growth depends on the subject to be protected. However, it is usually sufficient to apply 0.5 to 2500 ppm of the microbicide to the subject to be protected. Often, the microbicides are used in the subject after further dilution. For example,
The composition of the present invention is added to a metal working fluid concentrate, which is then further diluted. The amount of the composition of the present invention required to prevent microbial growth in the final metal working fluid diluent generally ranges from 5 to 5 in the final diluent.
The amount is such that 0 ppm of the microbicide is provided. In subjects such as undiluted paints, the amount of the composition of the present invention required to prevent microbial growth is such that generally 500 to 2500 ppm of the microbicide is provided. .

When the bioactive compound of the present invention is a marine antifouling agent, the composition of the present invention inhibits the growth of marine organisms by applying the composition on or in marine structures. Can be used to Depending on the specific marine structure to be protected, the compositions of the present invention can be added directly to the marine structure, can be applied directly to the marine structure, or can be added to the paint and then added to the marine structure. Paints can also be applied to offshore structures.

Suitable structures include boats, ships, oil platforms, piers,
iers), pilings, docks, elastic rubber and fishnets, etc.
It is not limited to these. The compositions of the present invention are typically added directly into the structure during manufacture, such as elastic rubber or fishnets. Direct application of the compounds of this invention is typically to structures such as fishnets or wood pilings. Also, the compositions of the present invention can be added to marine paints such as marine paints or varnishes.

When the composition of the present invention contains a marine antifouling agent,
The amount of the composition of the invention required to inhibit or prevent the growth of marine organisms is typically based on the weight of the structure to be protected or the weight of the paint to be applied, .1-30% by weight of the marine antifouling agent. When the composition of the present invention is added directly into a structure or applied directly onto a structure, the amount of antifouling agent suitable to prevent the growth of marine organisms is typically
The amount is such that 0.1-30% by weight, based on the weight of the structure, of the marine antifouling agent is provided. Preferably, the amount of the composition of the present invention is such that 0.5-20% by weight of marine antifouling agent is provided, such that 1-15% by weight of marine antifouling agent is provided. Is more preferable. When added to a paint, the amount of the composition of the present invention suitable to prevent the growth of marine organisms is typically 0.1-30% by weight, based on the weight of the paint, of a marine antifouling agent. Is the amount provided. 0.5-15% by weight of the composition of the invention
Preferably, the amount is such that 1 to 10% by weight of the marine antifouling agent is provided.

Generally, the compositions of the present invention, including the marine antifouling agent, are formulated in a carrier, for example, water; an organic solvent such as xylene, methyl isobutyl ketone, and methyl isoamyl ketone; or a mixture thereof. Added.

Direct application of the compositions of the present invention is by known means such as dipping, spraying, or coating.
Also, for example, a fishnet can be protected by immersing the fishnet in a composition comprising the composition of the present invention and a carrier, or by spraying the composition onto the fishnet.

Structures such as wood pilings and fishnets can be protected by adding the composition of the invention directly into the structure. For example, the composition of the present invention further containing a carrier, wood used for piling,
It can be applied by pressure treatment or vacuum impregnation.
These compositions can also be incorporated into the fishnet fibers during manufacture.

The marine paint contains a binder and a solvent and optionally other components. The solvent may be either an organic solvent or water. The compositions of the present invention are suitable for use in both solvent-based marine paints and water-based marine paints. Solvent-based marine paints are preferred.

Known binders can be utilized in marine antifouling coatings to which the compositions of the present invention have been added. Suitable binders include solvent-based polyvinyl chloride;
Solvent-based chlorinated rubber; solvent-based or aqueous-based acrylic resin; aqueous dispersion-based or solvent-based vinyl chloride-vinyl acetate copolymer system; butadiene-styrene rubber; butadiene-acrylonitrile rubber; Styrene-acrylonitrile rubber; drying oils such as linseed oil; asphalt; epoxies; siloxanes, but are not limited thereto.

The marine paints of the present invention may optionally contain one or more of the following materials: inorganic pigments, organic pigments or dyes, controlled release materials such as rosin. The water-based coating may also optionally contain the following materials: coalescents, dispersants, surfactants, rheology improvers, or adhesion promoters. Also, the solvent-based coating may optionally contain a bulking agent, a plasticizer, or a rheology modifier.

Typical marine paints comprise 2-20% by weight binder, up to 15% by weight rosin / modified rosin,
0.5-5% by weight plasticizer, 0.1-2% by weight anti-settling agent, 5-60% by weight solvent / diluent, 70% by weight or less cuprous oxide, 30% by weight or less ( Other than cuprous oxide)
Pigment and up to 15% by weight of marine antifouling agent.

Marine paints containing the compositions of the present invention can be applied to structures to be protected by any of a number of known methods. Suitable methods for application include spraying;
Examples include, but are not limited to, roll coating; brush coating; or dipping.

When the biologically active compound is a pesticide, the composition according to the invention can be applied to plants or soil or used as a seed treatment. The composition can be used directly and also as powders, granules, flowables,
It can be formulated as an emulsion, microemulsion, emulsion, or microemulsion, or can be encapsulated.

The following examples are provided to illustrate further various aspects of the present invention, but do not limit the scope of the invention. Example 1 Preparation of a Composition of the Invention A composition of the invention was prepared by the following general method. A solution or slurry of the calixarene compound in methanol or acetone was charged to the flask. To this solution or slurry was added a solution of 4,5-dichloro-2-n-octyl-3-isothiazolone dissolved in the same solvent as the calixarene compound. The amount of 4,5-dichloro-2-n-octyl-3-isothiazolone added is:
The final product was such that it contained 29-60% by weight, based on the weight of the composition, of 4,5-dichloro-2-n-octyl-3-isothiazolone. After thorough mixing, the solvent was removed at 50 ° C. under vacuum to give a solid or oil. The final product yield was 95-100%. The composition is shown in Table 1.

Calixarene compound A = 2,8,14,20-tetrapropylpentacyclo
[19.3.1.1^{3, 7}. 1^9,13.
1^{15, 19}] Octocosa-1 (25), 3, 5, 7
(28), 9, 11, 13 (27), 15, 17, 19
(26), 21,23-dodekaene-4,6,10,1
2,16,18,22,24-octol; B = 2,8,14,20-tetramethylpentacyclo
[19.3.1.1^3,7. 1^9,13.
1^{15, 19}] Octocosa-1 (25), 3, 5, 7
(28), 9, 11, 13 (27), 15, 17, 19
(26), 21,23-dodekaene-4,6,10,1
2,16,18,22,24-octol; C = 2,8,14,20-tetraphenylpentacyclo
[19.3.1.1^{3, 7}. 1^9,13.
1^{15, 19}] Octocosa-1 (25), 3, 5, 7
(28), 9, 11, 13 (27), 15, 17, 19
(26), 21,23-dodekaene-4,6,10,1
2,16,18,22,24-octol; D = 2,8,14,20-tetra-t-butylpentacene
Black [19.3.1.1] ^3,7. 1^9,13. 1
^{15, 19}] Octocosa-1 (25), 3, 5, 7 (2
8), 9, 11, 13 (27), 15, 17, 19 (2
6), 21,23-dodecaene-4,6,10,12,
16,18,22,24-octol.

[0042]

[Table 1]

Example 2 The release rate of the biologically active compound of the composition of Example 1 was measured by the following method. When all 4,5-dichloro-2-n-octyl-3-isothiazolone is released, 4,5-dichloro-2-n-octyl-3
Sample 2 was weighed in a 100 mL glass jar in an amount sufficient to give 20 mg / L isothiazolone.
In this solution, 1% deionized water containing 0.3% by weight of sodium dioctyl sulfosuccinate as a surfactant was added.
00 mL was added. The solution was then gently stirred.
0.5 mL aliquots are taken at various times,
Transferred to a centrifuge tube and centrifuged at 14,000 rpm for 3 minutes. The resulting clear aqueous layer was analyzed for 4,5-dichloro-2-n-octyl-3-isothiazolone. The centrifuge tube was then washed with 0.5 mL of fresh water / surfactant solution and the wash was returned to the glass jar. This operation did not lose any particles collected during sampling and kept the volume constant. Aliquots were analyzed by HPLC for the amount of 4,5-dichloro-2-n-octyl-3-isothiazolone released. 4,5-dichloro-2-n released
Table 2 shows the integrated% of -octyl-3-isothiazolone.

[0044]

[Table 2]

The above data shows that the composition of the present invention shows that
This shows that 5-dichloro-2-n-octyl-3-isothiazolone releases slowly over a long period of time.

Example 3 The composition of Example 1 was evaluated for controlling the release of bioactive molecules in marine paints. A blank paint, ie, a paint containing no bioactive molecules, was mixed with Sample 1.
The amount of sample added was such that the amount of 4,5-dichloro-2-octyl-3-isothiazolone in the paint was 5.6% by weight, based on the total dry weight of the paint. The control paint was 4,5-dichloro-2-octyl-3.
-Prepared by adding only isothiazolone. Apply the treated paint and control paint to a glass slide,
Dry in hood for 6 days. The slide was then immersed in a tank of synthetic seawater. Slides were collected after 14 days,
The paint film was extracted. The extract was analyzed by HPLC and the remaining 4,5-dichloro-2-octyl-3
-The amount of isothiazolone was measured. Table 3 shows the amount of 4,5-dichloro-2-n-octyl-3-isothiazolone released from the paint.

[0047]

[Table 3]

The above data clearly demonstrate that the compositions of the present invention release bioactive molecules slowly from paint films.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A01N 43/78 101 A01N 43/78 101 43/80 102 43/80 102

Claims (10)

[Claims] A controlled release composition comprising a biologically active compound and a calixarene compound having the following structural formula: Wherein X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² , Y ³ , and Y ⁴ are independently hydrogen, cyano, nitro, halo, (C ₁
—C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₂ )
—C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl,
Phenyl, substituted phenyl, (C ₇ -C ₁₀ ) aralkyl, substituted (C ₇ -C ₁₀ ) aralkyl, NR ² R ³ ,
It is selected from SR ^{4; X 1} and ^Y 1, ^{X 2} and ^Y 2, ^{X 3} and ^{Y 3,} and ^{X 4} and ^{Y 4} bonded to 5-membered - or 6-membered - may form a ring; R and ^{R 1} are independently _{hydrogen, (C} 1 -C ₈₎ alkyl, cyclopropyl, phenyl, substituted phenyl, _{(C 7} -
Selection R 2, ^{R 3,} and ^{R 4} are independently _{hydrogen, (C} 1 -C ₄₎ alkyl, phenyl, and substituted ^phenyl; C ₁₀₎ aralkyl is selected from substituted _(C 7 _{-C 10)} aralkyl N = 1-7, and m, o, p, and z are independently selected from 1-3. 2. The biologically active compound is: 5-chloro-2-methyl-3-isothiazolone; 2-methyl-3-isothiazolone; 2-n-octyl-3-isothiazolone;
5-dichloro-2-n-octyl-3-isothiazolone; 1,2-dibromo-2,4-dicyanobutane; methylenebis (thiocyanate); 2-thiocyanomethylthiobenzothiazole; tetrachloroisophthalonitrile; 5-bromo- 5-nitro-1,3-dioxane; 2
-Bromo-2-nitropropanediol; 2,2-dibromo-3-nitrilopropionamide; N, N'-dimethylhydroxyl-5,5'-dimethylhydantoin;
Bromochlorodimethylhydantoin; 1,2-benzisothiazolin-3-one; 4,5-trimethylene-2-
Methyl-3-isothiazolone; 5-chloro-2- (2,
4-dichlorophenoxy) phenol; 3,4,4'-
Trichlorocarbanilide; magnesium ethylenebisdithiocarbamate; zinc dimethyl dithiocarbamate; 2-methyl-4-t-butylamino-6-cyclopropylamino-s-triazine; 2,4,5,6-tetrachloroisophthalonitrile N, N-dimethyldichlorophenylurea; zinc ethylenebisdithiocarbamate; copper thiocyanate; N- (fluorodichloromethylthio) -phthalimide; N, N-dimethyl-N'-
Phenyl-N′-fluorodichloromethylthio-sulfamide; zinc 2-pyridinethiol-1-oxide; tetramethylthiuram disulfide;
6-trichlorophenylmaleimide; 2,3,5,6-
Tetrachloro-4- (methylsulfonyl) -pyridine;
3-iodo-2-propynyl butyl carbamate;
Diiodomethyl p-tolyl sulfone; bisdimethyldithiocarbamoyl zinc ethylenebisdithiocarbamate; phenyl (bispyridyl) bismuth dichloride; 2- (4-thiazolyl) -benzimidazole; pyridine triphenylborane; phenylamide; halopropargyl compounds; The composition of claim 1, wherein the composition is selected from the group consisting of alkoxyaryl-3-isothiazolones. 3. The biologically active compound is 2-methyl-3-isothiazolone; 5-chloro-2-methyl-3-isothiazolone; 2-n-octyl-3-isothiazolone;
5-dichloro-2-n-octyl-3-isothiazolone; benzisothiazolone; 4,5-trimethylene-3
3-Iodo-2-propynylbutyl carbamate; 5-chloro-2- (2,4-dichlorophenoxy) phenol; and 3,4,4'-trichlorocarbanilide. Item 3. The composition according to Item 2. 4. A method of preparing 2,8,14,20-tetrapropylpentacyclo [19.3.1.1 ^3,7 . ^19,13 . 1
^15,19 ] octacosa-1 (25), 3,5,7 (2
8), 9, 11, 13 (27), 15, 17, 19 (2
6), 21,23-dodecaene-4,6,10,12,
16, 18, 22, 24-octol; 2, 8, 14,
20-tetramethylpentacyclo [19.3.1.1]
^3,7 . 1 ^{9, 13.} 1 ^15,19 ] octacosa-1
(25), 3, 5, 7 (28), 9, 11, 13 (2
7), 15, 17, 19 (26), 21,23-dodecaene-4,6,10,12,16,18,22,24-
Octol; 2,8,14,20-tetraphenylpentacyclo [19.3.1.1 ^3,7 . ^19,13 . 1
^{15, 19} ] octacosa-1 (25), 3, 5, 7 (2
8), 9, 11, 13 (27), 15, 17, 19 (2
6), 21,23-dodecaene-4,6,10,12,
16,18,22,24-octol; and 2,8,
14,20-tetra-t-butylpentacyclo [19.
3.1.1 ^3,7 . ^19,13 . 1 ^15,19 ] octacosa-1 (25), 3,5,7 (28), 9,11,1
3 (27), 15, 17, 19 (26), 21, 23
Dodecaene-4,6,10,12,16,18,22,
The composition of claim 1, wherein the calixarene compound is selected from the group consisting of 24-octol; 5. The composition according to claim 1, wherein the weight ratio of the biologically active compound to the calixarene compound ranges from 0.1: 99.9 to 95: 5. 6. The weight ratio of the biologically active compound to the calixarene compound is in the range from 1:10 to 9: 1.
A composition as described. 7. Water, acetonitrile, ethyl acetate, butyl acetate, toluene, xylene, methanol, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethylene glycol, diethylene glycol,
The composition of claim 1, further comprising a carrier selected from the group consisting of propylene glycol and dipropylene glycol. 8. A method for preventing the growth of fungi, bacteria, algae, marine pollutants, and insects, comprising introducing the composition of claim 1 into the subject to be protected. 9. The object to be protected is a cooling tower; an air washer;
Mineral slurries; Pulp and paper processing fluids; Paper coatings; Adhesives; Caulks; Mactics; Sealants; Agricultural adjuvant preservatives; Building products; Cosmetics and toiletry products; Industrial or household compounding products; Soaps; Rinsing water for washing; Leather and leather products; Wood; Plastics; Lubricants; Hydraulic fluids; Medical instruments; Metal working fluids; Emulsions and dispersions; Conditioning fluids; coatings; petroleum processing fluids; fuels; oilfield fluids; photographic chemicals; printing fluids; 9. The method of claim 8, wherein 10. The method of claim 9, wherein the offshore structure is selected from the group consisting of a boat, an oil platform, a pier, a piling, a dock, an elastic rubber, and a fishnet.